Helga Davidowa

Altered responses to orexigenic (AGRP, MCH) and anorexigenic (alpha-MSH, CART) neuropeptides of paraventricular hypothalamic neurons in early postnatally overfed rats.

Food intake and energy expenditure are regulated by neuropeptides in the hypothalamus. While cocaine‐ and amphetamine‐regulated transcript (CART) peptide and melanocortins such as α‐melanocyte‐stimulating hormone (α‐MSH) are anorexigenic and increase energy expenditure, the endogenous melanocortin receptor antagonist agouti gene‐related protein (AGRP), melanin‐concentrating hormone (MCH) and neuropeptide Y (NPY) are orexigenic, anabolic peptides. Alterations in the regulatory balance may promote excessive weight gain. The action of these peptides on paraventricular hypothalamic neurons was studied in brain slices of overweight, adult rats previously subjected to early postnatal overfeeding in small litters of only three pups per mother, compared to 12 pups per dam in control litters. CART, melanocortins and NPY significantly excited paraventricular neurons of controls, whereas neurons of small‐litter rats were mainly inhibited. Inhibition was dominant following administration of AGRP, MCH and NPY. The altered responses of paraventricular neurons in adult small‐litter rats might reflect a general mechanism of neurochemical plasticity and ‘malprogramming’ of hypothalamic neuropeptidergic systems acquired during the postnatal critical differentiation period, thus leading to permanently altered function of these regulatory systems of body weight.

Decreased inhibition by leptin of hypothalamic arcuate neurons in neonatally overfed young rats

Rats neonatally overnourished due to a reduced litter size develop persisting overweight throughout life. A presumed mechanism leading to this ‘malprogramming’ consists of an acquired change of the responsiveness to leptin of the neuronal system regulating feeding behavior. The study reports significant differences in the effects of leptin on single unit activity of the arcuate nucleus in brain slices of normal compared wirh early postnatally overfed juvenile rats. The firing rate of arcuate neurons in normal rats was inhibited by leptin (Wilcoxon test p < 0.0001, n =42), whereas it was not changed in obese rats (Wt p = 0.24, n = 35). The reduced inhibition by leptin of arcuate neurons in neonatally overfed rats might indicate an acquired hypothalamic leptin resistance contributing to persistent hyperphagia and overweight.

5‐HT1A receptor‐mediated inhibition and 5‐HT2 as well as 5‐HT3 receptor‐mediated excitation in different subdivisions of the rat amygdala

The techniques of extracellular single cell recording and microiontophoresis were used to study the effects of serotonin (5‐HT) and of 5‐HT1A, 5‐HT2A/2C and 5‐HT3 receptor agonists on the spontaneous activity of amygdaloid neurons in rats anesthetized with urethane. The background discharge rate was modified by 5‐HT as well as by 5‐HT agonists in about two‐thirds of neurons tested in different nuclei of the amygdaloid complex. Whereas the 5‐HT2 and 5‐HT3 agonists significantly increased the neuronal discharge rate in nearly all subdivisions of the amygdala, the 5‐HT1A agonist significantly inhibited the firing rate. Co‐administration of bicuculline and 5‐HT receptor agonists prevented the 8‐OH‐DPAT‐induced increases in the firing rate in most cases tested, as well as the inhibitory effects of DOI or 2‐methyl‐5HT. Therefore, GABAergic interneurons seem to be involved in the mediation of serotonergic effects. The action of 5‐HT agonists on the neuronal discharge rate was blocked by different receptor‐specific antagonists. The results support the hypothesis that 5‐HT exerts control throughout the amygdala by acting at least on 5‐HT1A, 5‐HT2A/2C and 5‐HT3 receptors seemingly located both on projection and interneurons. Synapse 38:328–337, 2000.

Insulin resistance of hypothalamic arcuate neurons in neonatally overfed rats

Rats exposed to early postnatal overfeeding by rearing in small litters become hyperphagic, hyperleptinemic, and hyperinsulinemic throughout later life. Medial arcuate neurons are involved in body weight regulation. They were tested in brain slices of control and small-litter rats concerning differences in responses to insulin. Insulin induced suppression of firing in controls, whereas in small-litter rats inhibition was significantly reduced and activation increased. This could be observed in juvenile as well as adult rats. A &ggr;-aminobutyric acid type A receptor antagonist did not change the responses. Thus, negative feedback to the satiety signal insulin on medial arcuate neurons is reduced in neonatally overfed small-litter rats. This can be regarded as insulin resistance, which is induced during early development and persists in later life.

Inhibition by insulin of hypothalamic VMN neurons in rats overweight due to postnatal overfeeding

Single unit activity was studied in brain slices of normal and overweight adolescent rats, the latter grown up until weaning in small litters of three pups per mother (SL). Significantly fewer neurons of the ventromedial hypothalamic nucleus (VMN) were activated by insulin in overweight SL rats than in normal (NL) rats (χ2p < 0.01). Although there is no significant difference between NL and SL rats in the number of VMN neurons responsive to insulin, the neurons differ in the type of reaction. In overweight SL rats neurons were mainly inhibited by insulin (Wilcoxon test p < 0.0001, n = 45). This altered response to the satiety signal insulin in postnatally overnourished rats might contribute to their persisting hyperphagia and overweight.

Different responses of ventromedial hypothalamic neurons to leptin in normal and early postnatally overfed rats

Leptin is crucially involved in the central nervous regulation of body weight. Neurons of the ventromedial hypothalamic nucleus (VMH) express leptin receptors and signal satiety with increase in their firing. Normally, leptin mainly activates VMH neurons. Rats grown up in small litters (SL) develop persistent hyperphagia and obesity throughout life. We studied single unit activity in hypothalamic brain slices of juvenile SL rats overweight due to early postnatal overfeeding (Mann-Whitney U-test, P < 0.001). VMH neurons of normal rats were mainly activated by leptin (Wilcoxon test, P < 0.05, n = 39), whereas neurons of overweight SL rats were mainly inhibited (Wt, P < 0.001, n = 33). This clearly altered response to leptin in neonatally overnourished rats might contribute to their persistent overweight throughout life.

Action of urethane on dorsal lateral geniculate neurons

Light evoked neuronal responses of urethane anaesthetized rats were compared with those recorded in freely moving animals. The results demonstrate that urethane reduces the firing frequency, the response probability as well as the number of excitatory light evoked response phases. These changes are combined with a prolongation of the postexcitatory inhibitory phases. The latencies to diffuse flashes are increased in geniculate neuronal responses as well as in evoked potentials recorded from the visual cortex. A similar relation exists between diminution of late geniculate excitations and suppression of cortical photic afterdischarges.

Increased response to NPY of hypothalamic VMN neurons in postnatally overfed juvenile rats.

Rats postnatally overnourished due to a reduced litter size become persistently overweight. A presumed pathophysiological mechanism consists of a change in the activity and responsiveness to neuropeptides of the neuronal system regulating feeding behavior. This study aimed to find differences in the action of neuropeptide Y, orexin-A and cholecystokinin on single unit activity of the ventromedial hypothalamic nucleus in brain slices of normal and postnatally overfed juvenile rats. NPY inhibited significantly more neurons (15 of 23) of obese than of normal rats (6 of 27; p < 0.01, chi2). Orexin-A and CCK-8S mainly activated the neurons without significant differences between the groups. In conclusion, the stronger inhibition by NPY of VMN neurons which signal satiety might contribute to increased feeding behavior in postnatally overfed rats.

Hypothalamic ventromedial and arcuate neurons of normal and postnatally overnourished rats differ in their responses to melanin-concentrating hormone

Melanin-concentrating hormone (MCH) is a neuropeptide involved in regulation of food intake and body weight. The study aimed to detect possible differences in responses of hypothalamic ventromedial and arcuate neurons to MCH, depending on the short-term nutritional state (fed versus food-deprived) and on the long-term state in overweight rats due to early postnatal overnutrition. The effect of MCH on a single-unit activity was studied in brain slices of normal and overweight rats. The latter (n=16) were raised till weaning in small litters (SL) of 3 pups compared to 10 pups in control litters (CL) and gained significantly greater body mass. Whereas MCH in effective concentrations in the pico- to nanomolar range could increase or suppress the activity of ventromedial or arcuate neurons studied in male normal fed or food-deprived (24 h) rats, its action became shaped in an unidirectional way in overweight, hyperphagic rats. Medial arcuate neurons (n=25) from hyperphagic rats were predominantly activated by MCH (p<0.05, paired t-test). This effect differed significantly from that induced on neurons (n=27) of control rats. Ventromedial neurons (n=34) of overweight rats were predominantly inhibited. Activation of arcuate neurons may induce feeding in particular through release of neuropeptide Y (NPY). Inhibition of ventromedial neurons may contribute to reduced energy expenditure. The increased expression of one response type to MCH by a neuronal population in overweight, hyperphagic rats might reflect a general mechanism of neurochemical plasticity and also suggest a participation of the peptide in long-term regulation of food intake and body weight in this model of obesity.

Histamine reduces firing and bursting of anterior and intralaminar thalamic neurons and activates striatal cells in anesthetized rats.

Histamine is known to play a role in the regulation of waking behavior as well as in processes of memory and reinforcement. The striatum and thalamic nuclei as the intralaminar complex and the anterior group can be involved in these functions. Little is known about the action of histamine on neurons of these brain structures. Single unit activity was extracellularly recorded in rats anesthetized with urethane. Firing of anterior and intralaminar thalamic neurons that responded to iontophoretically administered histamine was predominantly reduced (Wilcoxon test (Wt), P<0.05, n=49 and 63, respectively), whereas striatal neurons were mainly activated by the drug (Wt, P<0.05, n=29). Thalamic neurons also significantly reduced the number of burst discharges and the proportion of spikes involved in bursts. The histaminergic effects could be blocked by H1 or H2 receptor antagonists. In conclusion, histamine may control waking behavior also via nonspecific thalamic nuclei and basal ganglia circuits. Through modulation of the transmission in the anterior thalamus it may exert an influence on learning and emotional processes.